Since 1996, the Boston University Alzheimer's Disease Center (BU ADC) Neuropathology Core has conducted and facilitated cutting-edge research on the neuropathology of Alzheimer's disease (AD) and is recognized internationally for outstanding contributions to neuropathological diagnosis and clinicopathological analysis. Under the consistent leadership of Dr. Ann McKee, the Core continues to provide advances in our understanding of preclinical AD, the contribution of microvascular injury to cognitive impairment, the effects of repetitive trauma on neurodegeneration, and the result of protracted aging on the brain. The BU ADC Neuropathology Core serves diverse brain donor cohorts, which include the internationally-renowned Framingham Heart Study (FHS), the Centenarian Study (CEN), and, most recently, the Center for the Study of Traumatic Encephalopathy (CSTE). Innovations include the collection of supplemental tissue, including eyes and spinal cord tissue, in addition to brain and cerebrospinal fluid. Our Neuropathology Core has pioneered standardized criteria for rating microvascular pathology to assess the contribution of gross and microvascular pathology to cognitive impairment. We were the first group to recognize the eariy neurofibrillary degeneration of the posterior visual association cortex in preclinical AD. Furthermore, the BU ADC Neuropathology Core infrastructure was leveraged to create the BU CSTE, which has provided groundbreaking research on the long-term neurodegenerative consequences of repetitive mild traumatic brain injury. We have defined the essential clinical and neuropathological features of Chronic Traumatic Encephalopathy (CTE), a progressive neurodegenerative disorder characterized by the accumulation of hyperphosphorylated tau and TDP-43 proteins. In the next cycle, we will assess the relationship between ischemic injury and cognitive status and validate the diagnostic criteria that distinguish CTE from other tauopathies and TDP-43 proteinopathies, including AD. Through institutional support from the Edith Nourse Rogers Memorial Veterans Hospital in Bedford, MA, the newly renovated neuropathology laboratories have doubled in size with state-of-the-art Leica equipment. Three histology technicians and a MD pathologist have been added, and we are currently recruiting an additional neuropathologist. Although there has been a dramatic expansion in the capabilities and institutional infrastructure in the past four years, none of these accomplishments could have taken place without the framework and personnel provided by the BU ADC Neuropathology Core, whose existence continues to be absolutely central to all our endeavors.